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Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy
BACKGROUND: Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251970/ https://www.ncbi.nlm.nih.gov/pubmed/25460005 http://dx.doi.org/10.1371/journal.pone.0113805 |
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author | Yee, Kristine Malliaras, Konstantinos Kanazawa, Hideaki Tseliou, Eleni Cheng, Ke Luthringer, Daniel J. Ho, Chak-Sum Takayama, Kentaro Minamino, Naoto Dawkins, James F. Chowdhury, Supurna Duong, Doan Trang Seinfeld, Jeffrey Middleton, Ryan C. Dharmakumar, Rohan Li, Debiao Marbán, Linda Makkar, Raj R. Marbán, Eduardo |
author_facet | Yee, Kristine Malliaras, Konstantinos Kanazawa, Hideaki Tseliou, Eleni Cheng, Ke Luthringer, Daniel J. Ho, Chak-Sum Takayama, Kentaro Minamino, Naoto Dawkins, James F. Chowdhury, Supurna Duong, Doan Trang Seinfeld, Jeffrey Middleton, Ryan C. Dharmakumar, Rohan Li, Debiao Marbán, Linda Makkar, Raj R. Marbán, Eduardo |
author_sort | Yee, Kristine |
collection | PubMed |
description | BACKGROUND: Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy. METHODS AND RESULTS: We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled (“dose optimization”) study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled (“pivotal”) study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo. CONCLUSIONS: Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration. |
format | Online Article Text |
id | pubmed-4251970 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-42519702014-12-05 Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy Yee, Kristine Malliaras, Konstantinos Kanazawa, Hideaki Tseliou, Eleni Cheng, Ke Luthringer, Daniel J. Ho, Chak-Sum Takayama, Kentaro Minamino, Naoto Dawkins, James F. Chowdhury, Supurna Duong, Doan Trang Seinfeld, Jeffrey Middleton, Ryan C. Dharmakumar, Rohan Li, Debiao Marbán, Linda Makkar, Raj R. Marbán, Eduardo PLoS One Research Article BACKGROUND: Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy. METHODS AND RESULTS: We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled (“dose optimization”) study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled (“pivotal”) study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo. CONCLUSIONS: Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration. Public Library of Science 2014-12-02 /pmc/articles/PMC4251970/ /pubmed/25460005 http://dx.doi.org/10.1371/journal.pone.0113805 Text en © 2014 Yee et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Yee, Kristine Malliaras, Konstantinos Kanazawa, Hideaki Tseliou, Eleni Cheng, Ke Luthringer, Daniel J. Ho, Chak-Sum Takayama, Kentaro Minamino, Naoto Dawkins, James F. Chowdhury, Supurna Duong, Doan Trang Seinfeld, Jeffrey Middleton, Ryan C. Dharmakumar, Rohan Li, Debiao Marbán, Linda Makkar, Raj R. Marbán, Eduardo Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy |
title | Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy |
title_full | Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy |
title_fullStr | Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy |
title_full_unstemmed | Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy |
title_short | Allogeneic Cardiospheres Delivered via Percutaneous Transendocardial Injection Increase Viable Myocardium, Decrease Scar Size, and Attenuate Cardiac Dilatation in Porcine Ischemic Cardiomyopathy |
title_sort | allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251970/ https://www.ncbi.nlm.nih.gov/pubmed/25460005 http://dx.doi.org/10.1371/journal.pone.0113805 |
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